跑步运动对APP/PS1小鼠内侧前额叶皮质及其小胶质细胞的作用

郭一静; 蒋林; 张钐钐; 朱琳; 周春妮; 张蕾; 肖倩; 何琦; 杨浩; 李静; 邓宇辉; 晁凤蕾; 唐勇

doi:10.16016/j.2097-0927.202110032

您当前的位置：

首页 >

文章列表页 >

跑步运动对APP/PS1小鼠内侧前额叶皮质及其小胶质细胞的作用

神经科学 | 更新时间：2026-01-09

- 跑步运动对APP/PS1小鼠内侧前额叶皮质及其小胶质细胞的作用
- Effects of running on medial prefrontal cortex and microglia in APP/PS1 mice
- 陆军军医大学学报 2022年44卷第9期页码：862-873
- 作者机构：
  
  400016 重庆，重庆医科大学基础医学院组织学与胚胎学教研室
- 作者简介：
  
  [晁凤蕾，E-mail: 116433520@qq.com CHAO Fenglei, E-mail: 116433520@qq.com
  [唐勇，E-mail: ytang062@163.com TANG Yong, E-mail: ytang062@163.com
- 基金信息：
  
  国家自然科学基金面上项目(81871073);重庆市自然科学基金面上项目(cstc2020jcyj-msxmX0125)
- DOI：10.16016/j.2097-0927.202110032
  中图分类号： R165;R322.81;R745.7
- 收稿：2021-10-09，
  
  修回：2021-11-11，
  
  纸质出版：2022-05-15
- 稿件说明：
移动端阅览
郭一静, 蒋林, 张钐钐, 等. 跑步运动对APP/PS1小鼠内侧前额叶皮质及其小胶质细胞的作用[J]. 陆军军医大学学报, 2022,44(9):862-873.

Yijing GUO, Lin JIANG, Shanshan ZHANG, et al. Effects of running on medial prefrontal cortex and microglia in APP/PS1 mice[J]. Journal of Army Medical University, 2022, 44(9): 862-873.
郭一静, 蒋林, 张钐钐, 等. 跑步运动对APP/PS1小鼠内侧前额叶皮质及其小胶质细胞的作用[J]. 陆军军医大学学报, 2022,44(9):862-873. DOI： 10.16016/j.2097-0927.202110032.

Yijing GUO, Lin JIANG, Shanshan ZHANG, et al. Effects of running on medial prefrontal cortex and microglia in APP/PS1 mice[J]. Journal of Army Medical University, 2022, 44(9): 862-873. DOI： 10.16016/j.2097-0927.202110032.

摘要

目的

研究跑步锻炼对阿尔茨海默症(Alzheimer′s disease，AD)模型小鼠内侧前额叶皮质(medial prefrontal cortex，mPFC)的体积变化、淀粉样β蛋白(amyloid beta protein，Aβ)和小胶质细胞的作用。

方法

将10月龄雄性APP/PS1转基因AD小鼠以简单随机法分为AD跑步组(给予为期4个月的主动跑步干预)和AD对照组，同时设相同月龄的雄性非转基因小鼠为正常对照组(AD对照组、正常对照组不做处理)。Morris水迷宫评估小鼠的空间学习和记忆能力；Y迷宫评估小鼠的工作记忆和参考记忆能力；体视学三维定量检测小鼠mPFC的体积和小胶质细胞(IBA1

)的总数；运用免疫荧光多重标记和激光共聚焦定量小鼠mPFC内活化小胶质细胞(CD68

/IBA1

)的数量、细胞面积和突起数量，Aβ斑块的数量和面积，IBA1

细胞内Aβ斑块的面积及其与Aβ斑块总面积的比值。

结果

AD跑步组和正常对照组在Morris水迷宫和Y迷宫中的表现明显优于AD对照组；AD对照组mPFC的体积较正常对照组显著性减小(

0.05)，而AD跑步组mPFC的体积较AD对照组显著性增大(

0.01)；AD对照组mPFC内IBA1

细胞和CD68

/IBA1

细胞较正常对照组显著增多(

0.05)。AD跑步组mPFC内IBA1

细胞和CD68

/IBA1

细胞较AD对照组显著性增多(

0.05)；AD跑步组mPFC内Aβ斑块总面积及平均面积较AD对照组显著性减小(

0.05)；Aβ周围的IBA1

细胞和CD68

/IBA1

细胞数量，mPFC内单个小胶质细胞及CD68

/IBA1

细胞的平均面积、IBA1

细胞内Aβ斑块的面积及其与mPFC内Aβ斑块的总面积的比值较AD对照组显著增多(

0.05)。

结论

跑步运动能够增加mPFC内CD68

小胶质细胞的数量，减少Aβ的沉积，延缓mPFC的萎缩，进而改善APP/PS1转基因AD小鼠空间学习和记忆能力以及工作和参考记忆能力。

Abstract

Objective

To investigate the effects of running on the volume change of medial prefrontal cortex (mPFC)

as well as amyloid beta protein (Aβ) and microglia in mPFC in mouse model of Alzheimer′s disease (AD).

Methods

Male APP/PS1 transgenic AD mice aged 10 months were randomly divided into AD running group (AD Run

given active running intervention for 4 months) and AD control group (AD Ctrl)

while non-transgenic mice at the same age were set as normal control group (Ctrl). The mice from the AD Ctrl and Ctrl groups received no treatment. Morris water maze test was us

ed to evaluate the abilities of spatial learning and memory of mice

and Y maze test was adopted to assess the working memory and reference memory in the mice. The volume of mPFC and the total number of microglia (IBA1

cells) in the mPFC were quantified with stereological methods. The number of activated microglia (CD68

/IBA1

cells) in the mPFC

cell body area

and process number of microglia

number and area of Aβ plaques

and area of Aβ plaques in IBA1

microglia were quantitatively measured by immunofluorescence multiple labeling and laser confocal microscopy

and the ratio of area of Aβ plaques in IBA1

microglia to the total area of Aβ plaques was calculated.

Results

The AD Run group and Ctrl group performed better than the AD Ctrl group in Morris water maze and Y maze tests. The volume of mPFC was significantly less in the AD Ctrl group than the Ctrl group (

0.05)

while that of the AD Run group was obviously larger than that of the AD Ctrl (

0.01). The AD Ctrl group had greatly larger numbers of IBA1

cells and CD68

/IBA1

cells in the mPFC than the Ctrl group (

0.05)

whereas the AD Run group had much larger numbers of those cells than the AD Ctrl group (

0.05). The total and average area of Aβ plaques in the mPFC was greatly diminished in the AD Run group than the AD Ctrl group (

0.05). In addition

the AD Run group also presented larger numbers of IBA1

cells and CD68

/IBA1

cells around Aβ

larger average body area of single microglia and CD68

/IBA1

cells

and elevated area of Aβ plaques in IBA1

cells

along with its ratio to the total area of Aβ plaques in mPFC improved (

0.05).

Conclusion

Running exercise increases the number of CD68

micr

oglia in the mPFC

reduces the Aβ plaques

delays the atrophy of mPFC

and thus improves the spatial learning and memory abilities as well as working memory and reference memory in APP/PS1 transgenic AD mice.

关键词

Keywords

references

2021 Alzheimer′s disease facts and figures[J]. Alzheimers Dement, 2021, 17(3): 327-406. DOI: 10.1002/alz.12328.

NORTON S, MATTHEWS F E, BARNES D E, et al . Potential for primary prevention of Alzheimer′s disease: an analysis of population-based data[J ] . Lancet Neurol, 2014, 13(8): 788-794. DOI: 10.1016/S1474-4422(14)70136-X.

MVLLER S, PREISCHE O, SOHRABI H R, et al . Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer′s disease[J ] . Alzheimers Dement, 2018, 14(11): 1427-1437. DOI: 10.1016/j.jalz.2018.06.3059.

ZHAO N, YAN Q W, XIA J, et al . Treadmill exercise attenuates aβ-induced mitochondrial dysfunction and enhances mitophagy activity in APP/PS 1 transgenic mice[J ] . Neurochem Res, 2020, 45(5): 1202-1214. DOI: 10.1007/s11064-020-03003-4..

TAPIA-ROJAS C, ARANGUIZ F, VARELA-NALLAR L, et al . Voluntary running attenuates memory loss, decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer′s disease[J ] . Brain Pathol, 2016, 26(1): 62-74. DOI: 10.1111/bpa.12255.

HOFFMANN K, SOBOL N A, FREDERIKSEN K S, et al . Moderate-to-high intensity physical exercise in patients with Alzheimer′s disease: a randomized controlled trial[J ] . J Alzheimers Dis, 2016, 50(2): 443-453. DOI: 10.3233/JAD-150817.

HOLTHOFF V A, MARSCHNER K, SCHARF M, et al . Effects of physical activity training in patients with Alzheimer′s dementia: results of a pilot RCT study[J ] . PLoS One, 2015, 10(4): e0121478. DOI: 10.1371/journal.pone.0121478.

BRAWEK B, SCHWENDELE B, RIESTER K, et al . Impairment of in vivo calcium signaling in amyloid plaque-associated microglia[J ] . Acta Neuropathol, 2014, 127(4): 495-505. DOI: 10.1007/s00401-013-1242-2.

NEWCOMBE E A, CAMATS-PERNA J, SILVA M L, et al . Inflammation: the link between comorbidities, genetics, and Alzheimer′s disease[J ] . J Neuroinflamm, 2018, 15(1): 276. DOI: 10.1186/s12974-018-1313-3.

SIETTE J, WESTBROOK R F, COTMAN C, et al . Age-specific effects of voluntary exercise on memory and the older brain[J ] . Biol Psychiatry, 2013, 73(5): 435-442. DOI: 10.1016/j.biopsych.2012.05.034.

XU Z Q, ZHANG L Q, WANG Q, et al . Aerobic exercise combined with antioxidative treatment does not counteract moderate- or mid-stage alzheimer-like pathophysiology of APP/PS 1 mice[J ] . CNS Neurosci Ther, 2013, 19(10): 795-803. DOI: 10.1111/cns.12139..

MAILLET D, RAJAH M N. Association between prefrontal activity and volume change in prefrontal and medial temporal lobes in aging and dementia: a review[J]. Ageing Res Rev, 2013, 12(2): 479-489. DOI: 10.1016/j.arr.2012.11.001.

SALAT D H, KAYE J A, JANOWSKY J S. Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease[J]. Arch Neurol, 2001, 58(9): 1403-1408. DOI: 10.1001/archneur.58.9.1403.

ANTZOULATOS E G, MILLER E K. Differences between neural activity in prefrontal cortex and striatum during learning of novel abstract categories[J]. Neuron, 2011, 71(2): 243-249. DOI: 10.1016/j.neuron.2011.05.040.

GAGNEPAIN P, VALLÉE T, HEIDEN S, et al . Collective memory shapes the organization of individual memories in the medial prefrontal cortex[J ] . Nat Hum Behav, 2020, 4(2): 189-200. DOI: 10.1038/s41562-019-0779-z.

EUSTON D R, GRUBER A J, MCNAUGHTON B L. The role of medial prefrontal cortex in memory and decision making[J]. Neuron, 2012, 76(6): 1057-1070. DOI: 10.1016/j.neuron.2012.12.002.

STOPFORD C L, THOMPSON J C, NEARY D, et al . Working memory, attention, and executive function in Alzheimer′s disease and frontotemporal dementia[J ] . Cortex, 2012, 48(4): 429-446. DOI: 10.1016/j.cortex.2010.12.002.

蒋林. 氟西汀对AD内侧前额叶皮质内神经元和突触病理改变的作用及作用机制研究[D]. 重庆: 重庆医科大学, 2019.

JIANG L. Effects of fluoxetine on the neuronal and synaptic pathological changes in the medial prefrontal cortex of the transgenic AD mice[D]. Chongqing: Chongqing Medical University, 2019.

Institute of Laboratory Animal Resources (US) Committee on Care and Use of Laboratory Animals. Guide for the care and use of Laboratory Animals[M]. 8th ed. Washingto (DC): National Academies Press (US). 2011: No. 85-23. DOI: 10.17226/12910.

YUEDE C M, ZIMMERMAN S D, DONG H, et al . Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer′s disease[J ] . Neurobiol Dis, 2009, 35(3): 426-32. DOI: 10.1016/j.nbd.2009.06.002.

HE Q, JIANG L, ZHANG Y, et al . Anti-LINGO-1 antibody ameliorates cognitive impairment, promotes adult hippocampal neurogenesis, and increases the abundance of CB1R-rich CCK-GABAergic interneurons in AD mice[J ] . Neurobiol Dis, 2021, 156: 105406. DOI: 10.1016/j.nbd.2021.105406.

VAN DE WERD H J, RAJKOWSKA G, EVERS P, et al . Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse[J ] . Brain Struct Funct, 2010, 214(4): 339-353. DOI: 10.1007/s00429-010-0247-z.

ZHANG L, TANG W, CHAO F L, et al . Four-month treadmill exercise prevents the decline in spatial learning and memory abilities and the loss of spinophilin-immunoreactive puncta in the Hippocampus of APP/PS 1 transgenic mice[J ] . Neurobiol Dis, 2020, 136: 104723. DOI: 10.1016/j.nbd.2019.104723..

YOUNG K, MORRISON H. Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ[J]. J Vis Exp, 2018(136). DOI: 10.3791/57648.

BAIK S H, KANG S, LEE W, et al . A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer′s disease[J ] . Cell Metab, 2019, 30(3): 493-507. e6. DOI: 10.1016/j.cmet. 2019.06.005.

CUMMINGS J, LEE G, ZHONG K, et al . Alzheimer′s disease drug development pipeline: 2021[J ] . Alzheimers Dement (N Y), 2021, 7(1): e12179. DOI: 10.1002/trc2.12179.

GODEFROY O, MARTINAUD O, VERNY M, et al . The dysexecutive syndrome of Alzheimer′s disease: the GREFEX study[J ] . J Alzheimers Dis, 2014, 42(4): 1203-1208. DOI: 10.3233/JAD-140585.

WOODWARD M C, ROWE C C, JONES G, et al . Differentiating the frontal presentation of Alzheimer′s disease with FDG-PET[J ] . J Alzheimers Dis, 2015, 44(1): 233-242. DOI: 10.3233/JAD-141110.

张蕾. AD早期行为学、Aβ和白质的改变及跑步锻炼能否延缓这些改变进程的探讨[D]. 重庆: 重庆医科大学, 2014.

ZHANG L. The early changes of behavior and amyloid and the white matter in Alzheimer′s disease and the effects of exercise on the behavior and the white matter in Alzheimer′s disease[D]. Chongqing: Chongqing Medical University, 2014.

蒋林. 跑步锻炼对早期APP/PS1转基因AD小鼠海马各亚区内神经元数量的影响[D]. 重庆: 重庆医科大学, 2015.

JIANG L. Effects of exercrise on the neurons in the Hippocampu s of early APP/PS 1 transgenic mouse[D ] . Chongqing: Chongqing Medical University, 2015.

CHAO F L, ZHANG Y, ZHANG L, et al . Fluoxetine promotes hippocampal oligodendrocyte maturation and delays learning and memory decline in APP/PS 1 mice[J ] . Front Aging Neurosci, 2020, 12: 627362. DOI: 10.3389/fnagi.2020.627362..

KRAEUTER A K, GUEST P C, SARNYAI Z. The Y-maze for assessment of spatial working and reference memory in mice[J]. Methods Mol Biol, 2019, 1916: 105-111. DOI: 10.1007/978-1-4939-8994-2_10.

MILLER E K, LUNDQVIST M, BASTOS A M. Working memory 2.0[J]. Neuron, 2018, 100(2): 463-475. DOI: 10.1016/j.neuron.2018.09.023.

ITTNER A, ITTNER L M. Dendritic tau in Alzheimer′s disease[J]. Neuron, 2018, 99(1): 13-27. DOI: 10.1016/j.neuron.2018.06.003.

HICKMAN S, IZZY S, SEN P, et al . Microglia in neurodegeneration[J ] . Nat Neurosci, 2018, 21(10): 1359-1369. DOI: 10.1038/s41593-018-0242-x.

VOGELS T, MURGOCI A N, HROMÁDKA T. Intersection of pathological tau and microglia at the synapse[J]. Acta Neuropathol Commun, 2019, 7(1): 109. DOI: 10.1186/s40478-019-0754-y.

SALTER M W, STEVENS B. Microglia emerge as central players in brain disease[J]. Nat Med, 2017, 23(9): 1018-1027. DOI: 10.1038/nm.4397.

CONDELLO C, YUAN P, GRUTZENDLER J. Microglia-mediated neuroprotection, TREM2, and Alzheimer′s disease: evidence from optical imaging[J]. Biol Psychiatry, 2018, 83(4): 377-387. DOI: 10.1016/j.biopsych.2017.10.007.

RANSOHOFF R M. Apolarizing question: do M1 and M2 microglia exist?[J]. Nat Neurosci, 2016, 19(8): 987-991. DOI: 10.1038/nn.4338.

MATSUMURA A, SUZUKI S, IWAHARA N, et al . Temporal changes of CD68 and α7 nicotinic acetylcholine receptor expression in microglia in Alzheimer′s disease-like mouse models[J ] . J Alzheimers Dis, 2015, 44(2): 409-423. DOI: 10.3233/JAD-141572.

UNGER M S, SCHERNTHANER P, MARSCHALLINGER J, et al . Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS 1 transgenic mice[J ] . J N euroinflamm, 2018, 15(1): 274. DOI: 10.1186/s12974-018-1304-4..

HENDRICKX D A E, VAN EDEN C G, SCHUURMAN K G, et al . Staining of HLA-DR, Iba1 and CD68 in human microglia reveals partially overlapping expression depending on cellular morphology and pathology[J ] . J Neuroimmunol, 2017, 309: 12-22. DOI: 10.1016/j.jneuroim.2017.04.007.

NAYAK D, ROTH T L, MCGAVERN D B. Microglia development and function[J]. Annu Rev Immunol, 2014, 32: 367-402. DOI: 10.1146/annurev-immunol-032713-120240.

COLONNA M, BUTOVSKY O. Microglia function in the central nervous system during health and neurodegeneration[J]. Annu Rev Immunol, 2017, 35: 441-468. DOI: 10.1146/annurev-immunol-051116-052358.

MANDREKAR S, JIANG Q, LEE C Y, et al . Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis[J ] . J Neurosci, 2009, 29(13): 4252-62. DOI: 10.1523/JNEUROSCI.5572-08.2009.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

甲基莲心碱通过抑制ROS/NLRP3/Caspase-1通路减少小胶质细胞焦亡并改善帕金森病神经炎症

SOCS3通过抑制NF-κB信号通路介导的小胶质细胞炎症反应改善帕金森病神经损伤

突触融合蛋白17改善Aβ31-35诱导的小鼠海马神经细胞死亡

WTAP通过调控SIRT1诱导小胶质细胞M1型极化的研究

跑步锻炼延缓APP/PS1双转基因小鼠内侧前额叶皮质树突棘数量的丢失